A major focus of drug abuse research is understanding the molecular adaptations caused by drugs of abuse that lead to addiction. Recent studies have focused attention on the important role that long-lasting aversive consequences of drug withdrawal play in this process. As immediate early genes play a critical role in mediating enduring forms of synaptic plasticity,we have initiated studies aimed at assessing whether one of these, Narp, may be involved in the long-lasting effects induced by drug exposure or withdrawal. We have chosen Narp for study because in vitro studies indicate that it is involved in clustering AMPA receptors and synapse formation, which have been implicated in several drug-induced adaptations. In preliminary studies we have found that Narp is selectively induced in the extended amygdala in response to opiate withdrawal. As the extended amygdala plays a key role in the aversive consequences of drug withdrawal, we plan to test the hypothesis that Narp mediates acquisition of this learned behavior. Accordingly, we will: (a) Determine whether suppressing Narp expression or action alters the aversive effects of opiate withdrawal, (b) Determine if Narp mediates synapse remodeling after opiate withdrawal. An improved understanding of the molecular mechanisms subserving drug addiction will help direct a more rational approach to looking for effective treatments. We have identified a putative mediator (a protein known as Narp) of drug withdrawal, a dysphoric state that helps sustain addiction. Using genetically-engineered Narp-deficient mice and viral vectors that suppress Narp expression we plan to evaluate Narp's role in this process.